The long-term goal of our laboratory is to elucidate the role of hyperthermia in the acute and chronic toxicities associated with MDMA exposure. The objective of this particular application, which is the next step toward attainment of our long-term goal, is to determine the central mechanisms and consequences of the hyperthermia induced by MDMA. We suggest that MDMA induces the central release of dopamine (DA) and (NE). The increased release of DA and/or NE results in D1 and alpha1-receptor (respectively) activation within the hypothalamic-pituitary-thyroid (HPT) axis and hyperthermia. The initially released DA is then deaminated by monoamine oxidase-B (MAO-B) resulting in excessive free-radical production and uncoupling protein (UCP) activation further facilitating MDMA mediated DA release and hyperthermia. Therefore creating a vicious cycle that results in further serotonergic neurotoxicity. The three specific aims of this proposal are as follows: (1) to identify the link between hyperthermia, central DA release and MDMA-mediated serotonergic neurotoxicity; (2) to characterize the cellular mechanisms by which MDMA activates the HPT axis; (3) to characterize the role of brain uncoupling protein activity in mediating MDMA induced neurotoxicity. The research proposed in this application is significant, because understanding the mechanisms and consequences behind MDMA-mediated hyperthermia will assist in identifying several new targets for the therapeutic treatment of MDMA induced toxicities.